Auto-ligating oligonucleotide compounds

Abstract

The invention provides compositions and a method for delivering an antisense compound or probe to a target polynucleotide. The compositions of the invention comprise a plurality of compounds each having an oligonucleotide moiety from about 4 to 12 monomers in length whose 3' and/or 5' termini have been modified by the addition of one or more terminal binding moieties. Whenever the oligonucleotide moieties specifically anneal to a target polynucleotide in a contiguous end-to-end fashion, the terminal binding moieties are capable of spontaneously interacting with one another to form a covalent linkages or stable complexes so that an effective antisense compound or probe is formed. The invention facilitates the delivery of antisense compounds to their targets and reduces the likelihood of nonspecific binding to non-target structures.

I claim: 
     
       1. A polynucleotide binding composition comprising: two to five components with an overall length of 12 to 120 nucleotides, each component comprising: (1) an oligonucleotide moiety comprising at least 6 nucleotides, and   (2) at least one terminal binding moiety linked by a short flexible linker having no more than from 2 to 8 carbon atoms to a 5' or 3' terminus of said oligonucleotide moiety,     each terminal binding moiety being a member of a pair of terminal binding moieties that spontaneously forms a stable non-covalent complex with one another when said components of said composition specifically bind to a target polynucleotide in a contiguous end-to-end fashion such that each pair of terminal binding moieties is brought into juxtaposition.   
     
     
       2. The polynucleotide binding composition of claim 1 wherein the number components is in the range of from 2 to 3 and wherein said oligonucleotide moiety of each component has a length in the range of from 6 to 40 monomers. 
     
     
       3. The polynucleotide binding composition of claim 1 selected from the group of polynucleotide binding compositions defined by the formulas:   O.sub.1 --X.sub.1 X.sub.2 --O.sub.2,       O.sub.1 --X.sub.1 X.sub.2 --O.sub.2 --Y.sub.1 Y.sub.2 --O.sub.3,       O.sub.1 --X.sub.1 X.sub.2 --O.sub.2 --Y.sub.1 Y.sub.2 --O.sub.3 --Z.sub.1 Z.sub.2 --O.sub.4, and       O.sub.1 --X.sub.1 X.sub.2 --O.sub.2 --Y.sub.1 Y.sub.2 --O.sub.3 --Z.sub.1 Z.sub.2 --O.sub.4 --W.sub.1 W.sub.2 --O.sub.5,     wherein O 1 , O 2 , O 3 , O 4 , and O 5  are oligonucleotide moieties and X 1 , X 2  ; Y 1 , Y 2  ; Z 1 , Z 2 , and W 1 , W 2  are pairs terminal binding moieties.   
     
     
       4. The polynucleotide binding composition of claim 1 with the formula:   O.sub.1 --X.sub.1 X.sub.2 --O.sub.2,     wherein O 1  and O 2  are oligonucleotide moieties and X 1  and X 2  are a pair of terminal binding moieties.   
     
     
       5. The polynucleotide binding composition of claim 3 wherein said short flexible linker is selected from the group consisting of phosphate, phophoramidate, hydroxyurethane, carboxyaminoalkyl and carboxyaminoalkylphosphate. 
     
     
       6. The polynucleotide binding composition of claim 3 wherein one or more of said pairs of terminal binding moieties form a hydrophobic complex. 
     
     
       7. The polynucleotide binding composition of claim 6 wherein X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , W 1 , and W 2  are selected from the group consisting of alkanes, fatty acids, fatty alcohols, steroids, waxes, and fat-soluble vitamins, wherein said X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , W 1 , and W 2  has no more than 20 to 40 carbon atoms. 
     
     
       8. The polynucleotide binding composition of claim 7 wherein X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , W 1 , and W 2  are each cholesterol. 
     
     
       9. The polynucleotide binding composition of claim 4 wherein X 1  is a steroid and X 2  is asteroid. 
     
     
       10. The polynucleotide binding composition of claim 9 wherein said steroids are cholesterol molecules. 
     
     
       11. The polynucleotide binding composition of claim 9 wherein said oligonucleotide moieties are antisense oligonucleotides complementary to a c-myc gene. 
     
     
       12. A polynucleotide binding composition of claim 9 wherein said steroids are chloesterol molecules attached to said short flexible linker at C 3  positions. 
     
     
       13. The polynucleotide binding composition of claim 5 wherein said short flexible linker is either carboxyaminoalkyl or carboxyaminoalkyl phosphate containing 2 to 8 carbon atoms.